The prior art recognizes that peptide transport systems are one mechanism by which chemical substances are carried into the cell membrane of an infecting organism. It has been postulated that both dipeptide and oligopeptide transport systems are present in the cell membrane, for example, in the cell membrane of Escherichia coli; B. N. Ames, Proc. Nat. Acad. Sci. OSH 70 456 (1973) or C. Gilvarg, Nature, the New Biology 241 161 (1973). The dipeptide transport system is more specific in its ability to transport than is the oligopeptide transport system.
Peptide transport systems are widespread in both procaryotic and eukaryotic microorganisms. A prodrug which can be transported per se through the cell membrane of infecting organisms via such a permease system and, then, releases the drug within the cell would possess enhanced activity.
A number of synthetic derivatives have been prepared to take advantage of this transport system such as those described by M. M. Ponpipom, et al., J. Med. Chem. 24 1388 (1981), European Patent Office application No. 38,541 or C. Philip, et al., PCT application, W0 81/01145. Some of these types of compounds were designed to limit toxicity or to achieve more specific biological activity. Such compounds of the prior art either are limited in scope or are aimed at being biologically active without degradation at the receptor site, that is, in the transport form, due to their resistance to intracellular peptidases. For example, the cited Philip publication discloses anti-tumor moieties which are covalently attached to a polypeptide. A covalently bound group must be active per se. This differs from the present invention in which the warhead or biologically active group is reversibly attached.
A number of potentially useful chemotherapeutic agents are present in the prior art which are impermeant or poorly permeant to the cell membrane of an infecting organism. The impermeant nature of these compounds may be either due to the inherent physico-chemical properties of the compounds or due to an acquired resistance to the drug by the permease system of the cell membrane of the target species.